Quality of Substances for Pharmaceutical Use: The EDQM Certification of Suitability to the European Pharmacopoeia Monographs (CEP) Dr. Susanne Keitel DIA

Quality of Substances for Pharmaceutical Use: The EDQM Certification of Suitability to the

European Pharmacopoeia Monographs (CEP)

Quality of Substances for Pharmaceutical Use: The EDQM Certification of Suitability to the

European Pharmacopoeia Monographs (CEP)

Dr. Susanne KeitelDIA Workshop on CEPs

Hyderabad, 5 September 2009

Dr. Susanne Keitel, 05/09/2009 ©2009 EDQM, Council of Europe, All rights reserved 22

SummarySummary

• Legal Background

• CEP versus ASMF

• How it works

• How to apply

• Certification Inspection Programme

• Exchanging information/advice, communication opportunities


Legal BackgroundLegal Background

Directive 2003/63/EC “Whereases”

(5) With respect to the quality part of the dossier, all monographs including general monographs and general chapters of the European Pharmacopoeia are applicable.


Directive 2003/63/ECDirective 2003/63/ECChapter 3.2 Content: basic principles and

requirements

(5) The monographs of the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. In respect of other substances, each Member State may require observance or its own national pharmacopoeia…


Directive 2003/63/ECDirective 2003/63/EC….However, where a material in the EP… has been

prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described. In cases where a specification contained in a monograph of the EP… might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorisation holder…


Directive 2003/63/ECDirective 2003/63/EC… The competent authorities shall inform the

authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.


Directive 2003/63/ECDirective 2003/63/EC(7) Where the active substance and/or raw and

starting material or excipient(s) are the subject of a monograph of the EP, the applicant can apply for a certificate of suitability that, where granted by the EDQM, shall be presented in the relevant section of the Module. Those certificates of suitability … are deemed to replace the relevant data of the corresponding sections described in the Module…


Directive 2003/63/ECDirective 2003/63/EC… The manufacturer shall give the assurance in

writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines.


Options for Submitting API InformationOptions for Submitting API Information

Certificate of suitability (CEP)Active Substance Master File (ASMF/EDMF)Substance Part of CTD


NfG CHMP/QWP/297/97 rev. 1 corr“Summary of requirements for active substances in the quality part of the dossier”

NfG CHMP/QWP/297/97 rev. 1 corr“Summary of requirements for active substances in the quality part of the dossier”

2.1 Certificate of suitabilitySince this procedure requires a Ph. Eur. monograph, it is used for existing substances and the guideline states : “ where applicable, option 2.1 has the advantage of generally avoiding any subsequent reassessment ”

2.2 Active substance Master File (ASMF)2.3 Full details of manufacture in licence application

Since these procedures do not require a Ph. Eur. monograph they can be used for new substances; but may also be used for existing substances.


Differences between CEP & ASMFDifferences between CEP & ASMF

- Scope:

• CEP : pharmacopoeial substances only,

-> active substances or excipients

• ASMF : active substances only,

-> new or pharmacopoeial



- Specificity of ASMF:• Full dossier sent by manufacturer of API to National

authorities• Applicants part sent by manufacturer of API to MA

applicant or holder of medicinal Product• Letter of access (to be sent by manufacturer of API)• Assessment of ASMF by each national authority in

the context of assessing a specific marketing authorisation application or variation for medicinal products



- Assessment of CEP applications:• Single evaluation centralised at EDQM

• By assessors nominated by national authorities

• Independent from marketing applications of medicinal products

• Certificate including annexes (additional tests to be performed) granted to manufacturer of active substance who supplies it to its users


Certificate of SuitabilityCertificate of Suitability

Provides:• Savings of time and resources• Confidentiality of data (as ASMF):

– Application submitted directly to EDQM by the applicant

• Facilitates management of marketing authorisation applications and variations

• CEP accepted in all Ph. Eur. commission countries (36) + others (eg. Canada (MoU 03/2007), Australia, Morocco, Tunisia, New Zealand etc.)


Regulatory backgroundRegulatory background

Directive 2003/63/EC and the various quality guidelines give options on how to fulfil the same basic requirements.

The information required is the same regardless of the route selected (CEP or ASMF or marketing autorisation application)


Scope of the Certification procedureScope of the Certification procedure

- Substances described in monographs in the Ph. Eur.Active substances, excipients, herbal drugs / herbalpreparations “Chemical” CEP

- Products with risk of TSE (SM, intermediates, reagents,..) “TSE “CEP

- Substances described in monographs in the Ph. Eur.and with risk of TSE “Double “CEP

Open to any manufacturer regardless of geographicalorigin


Out of Scope of the Certification procedureOut of Scope of the Certification procedure

- Biologicals- Human tissues derivatives- Finished products


Certification: organisationCertification: organisation

• Steering Committee

• Technical Advisory Boards (TAB)Chemical

TSE

Herbals

• Assessors

• Certification Secretariat


Certification Steering CommitteeCertification Steering Committee

• Chair Joint CHMP/CVMP Quality Working Party• Chair CHMP Biologics Working Party• Chair CVMP Immunologicals Working Party• Chair Committee on Herbal Medicinal Products• Chair GMP/GDP Inspectors Working Group• Representative of EC Pharmaceutical Unit• Representative of EMEA • Chair European Pharmacopoeia Commission• Chairs Technical Advisory Boards• Representative of non-EU/EEA licensing authorities• Director EDQM & Healthcare• Possibility to co-opt relevant expert(s)


Steering Committee - RoleSteering Committee - Role

• Monitor running of Certification procedure

• Appointment of assessors• Appointment of Technical Advisory Boards

(TABs) and their Chairpersons• Definition of policy• Review and comment on issues raised by

TABs• Co-ordination of issues between the

represented parties


Technical advisory boards (TABs)Technical advisory boards (TABs)

• Consist of experienced assessors involved in the CEP procedure for a substantial time

Role

• To take decisions on technical matter• To assist assessors in case of doubt or

disagreement• To prepare technical guidance• To identify technical/scientific problems and seek

advice of SC


Assessors and secretariatAssessors and secretariat

• “Independent” Assessors (about 65 from 14 countries)– Role: evaluation of dossiers

• Certification Secretariat (EDQM scientific and administrative staff )

– Role : execution of the procedure and co-ordination

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NL

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New application requires:New application requires:

1. Application form (for new application)

2. Signed Quality Overall Summary (+ e-version as Word file preferably)

For templates of 1 & 2, visit:www.edqm.eu / Certification / New Applications

3. CV of expert who wrote QOS



4. Dossier :• 1 copy in English (preferably) or French • CTD format

Visit www.edqm.eu / Certification / New Applications:

- Content of the Dossier for Chemical CEP (PA/PH/CEP (04) 1, 4R) : comparable to ASMF or 3.2.S of CTD



4. Dossier (continued) :Visit www.edqm.eu / Certification / New Applications:

- Content of a dossier for a substance for TSE risk assessment (PA/PH/CEP (06) 2) :requirements from Ph. Eur. general chapter 5.2.8 (= EU nfg)

- Content of a dossier for herbal drugs and herbal drugs preparation - quality evaluation (PA/PH/CEP 026)

- Certificates of Suitability for sterile active substances (PA/PH/Exp. CEP/T (06) 13, 1R)


Confidentiality Aspects

• CEP dossiers submitted directly by applicant– No applicant (open) part (≠ ASMF)

• Independent from any marketing authorisation application

• Archived in a specific restricted area (EDQM)• Assessment on the premises of EDQM by two

assessors appointed by the steering committee• Certificate granted independently of any product

licence application.• Certificate may be supplemented with appropriate

specific data and is only supplied to applicant


How long does it take?How long does it take?

• Timeframes:– Applicant notified by EDQM on the

assessment conclusion within 5 months of receipt of new dossier

– Responses from applicant expected within 6 months for original demand

– Applicant notified by EDQM on the assessment conclusion within 4 months of receipt of any response containing additional information

– Responses from applicant expected within 3 months for any subsequent demand

– …


Certificates of SuitabilityCertificates of Suitability

• > 3500 applications since procedure launched

• > 6400 certificates granted (includes revisions, renewals)

• ~ 2160 valid certificates

• > 760 substance monographs involved

• …


Certificates of SuitabilityCertificates of Suitability

… > 900 manufacturers from 56 countries worldwide

Repartition of manufacturing sites covered by CEPs (2008)

Europe41%

Asia38%

America15%

Pacific zone4%

Middle East1% Africa

1%


Certification: benefitsCertification: benefits

• Single assessment

• Harmonised assessment

• Replaces Active Substance Master File

• Savings of time and resources

• Updating of monographs (impurities)

• Revision of monographs (new or replacement test methods)


The certificate of suitability :

• Certifies that the quality of a given substance can be suitably controlled by the PhEur monograph - with additional tests if necessary.

• It DOES NOT certify that a batch or batches of the substance complies with the Pharmacopoeia monograph.

• It IS NOT a GMP certificate


Is a CEP valid ?Is a CEP valid ?

• www.edqm.eu / Databases• www.edqm.eu / Databases

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/

http://www.edqm.eu/


Is a CEP valid ?Is a CEP valid ?

Full CEP numberFull CEP numberStatusStatus

Holder nameHolder name Issue date of the current CEPIssue date of the current CEP


Certification Inspection programmeCertification Inspection programme


EU pharmaceutical legislationEU pharmaceutical legislation

Marketing autorisation holder (MAH) responsible for the quality of the medicinal product

MAH has to qualify/audit supplier(s)

Qualified Person of manufacturer(s) to certify GMP compliant manufacture of all API used in marketing autorisation application and/or relevant variations


Certification InspectionsCertification Inspections

In application of Directive 2001/83/EC as amended (Article 111) and Directive2001/82/EC as amended (Article 80)

A Mandate is given to EDQM (by EC) toestablish an annual programme for inspections

– Inspection inside and outside Europe– Manufacturing sites and brokers/distributors

holding CEPs– Authorities to be notified of issues arising


Exchanging information/advice, communication opportunities

Exchanging information/advice, communication opportunities


General questions on CEP procedure & its requirements ?General questions on CEP procedure & its requirements ?


Technical Advice meetingTechnical Advice meetingPossible i.e. when need to clarify requirements of CEPprocedure / complex schemes / specific questions:

– prior to or during the submission of an application for a new CEP or for its subsequent revision or renewal

– To meet CEP Division representatives– Need to apply in advance (at least 1 month)– Procedure and application form on the web– 1-2 sessions/month at EDQM premises (written

response, or telephone conference may also be possible)

– Fee of 1000 euros / Meeting length 1 hour


Technical Advice meetingTechnical Advice meeting


One-to-One meetingsOne-to-One meetings

- Same scope as technical advice meeting

- but organised during a conference or an exhibition

- Meeting length generally 15 to 30 minutes- Registration at least 1 week before event- Procedure and application form on the web -

specific for each event - Fee specific for each event


One-to-One meetingsOne-to-One meetings- Check “Events” pages of EDQM websitewww.edqm.eu


AcknowledgementsAcknowledgements

My special thanks to my colleagues from the Certification Division at the EDQM:

• Corinne Pouget ([email protected])• Hélène Bruguera ([email protected])• Patricia Oelker ([email protected])• And all the other 30 staff members of the CEP division

mailto:[email protected]
















Thank you!Thank you!

Documents

Quality of Substances for Pharmaceutical Use: The EDQM Certification of Suitability to the European Pharmacopoeia Monographs (CEP) Dr. Susanne Keitel DIA